Neurodegeneration represents a major public health issue as life expectancy increases. As of today, it concerns 1 individual out of 4 in Europe and represents about 800 billion euros of health expenditures. Presently, it is commonly accepted that the BBB is the sole line of defense of the CNS, restricting access to the parenchyma to peripheral attacks in the context of neuro-degeneration. However, with EFHHBBBMS, we bring a different perspective on CNS barrier organization, unveiling the existence of two independent, dissociable effects of the astrocyte and endothelial barriers in the CNS. For the first time, we demonstrate that BBB breakdown is sufficient to induce chronic barrier properties at the Glia Limitans and we highlight a crosstalk from endothelial cells to astrocytes which restrict access to the parenchyma to plasmatic proteins and inflammatory cells during neuropathology. Thus explain that the main approach which focuses on targeting BBB to limit or to facilitate access to the parenchyma has failed so far as it is more likely that playing on BBB status impact Glia Limitans barrier properties. Consequently, on a large scale, our project has wide implications for CNS access in neuropathology as well as drug delivery by manipulating both the BBB and Glia Limitans in combination. Indeed, taking into account both components of the gliovascular unit is of translational interest notably to limit CNS parenchymal access to pathogenic agents by strengthening the Glia Limitans once the BBB is open, in cardiovascular diseases such as brain ischemic strokes, neuro-infections and neuro-degeneration (Parkinson’s/Alzheimer’s diseases, vascular dementia) or to facilitate parenchymal access to drugs, by opening the BBB and Glia Limitans together, in CNS tumor treatment. Along similar lines, it is unknown how the barrier properties of the Glia Limitans may impact the pharmacokinetics of drugs that must enter the CNS parenchyma in conditions such as multiple sclerosis, which may account for treatment failure.
To highlight the project progression, we regularly applied to congresses related to our field (neurovascular biology, neuropathology and Hh pathway); amongst others, we participated to international (International Vascular Biology Meeting) and national conferences (Société d’Etude des Interfaces Sang Cerveau and the Société Française d’Angiogenèse). It gave us the opportunity to present the project to our pairs, using different supports (posters and power point presentations), to get a critical lecture and new perspectives for our research and to develop our network among some of the most talented researchers worldwide.
